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Targeting the Cannabinoid and Mu Opioid Receptors with Heterodimerized and Allosteric Ligands

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Targeting the Cannabinoid and Mu Opioid Receptors with Heterodimerized and Allosteric Ligands Targeting the cannabinoid and mu opioid receptors with heterodimerized and allosteric ligands Ph.D. Thesis Szabolcs Dvorácskó Supervisor: Dr. Csaba Tömböly Universitiy of Szeged, Faculty of Medicine Doctoral School of Theoretical Medicine Laboratory of Chemical Biology, Institute of Biochemistry Biological Research Center of the Hungarian Academy of Sciences Szeged, Hungary 2019 TABLE OF CONTENTS LIST OF PUBLICATIONS ...................................................................................................... i ABBREVIATIONS ................................................................................................................. iv ACKNOWLEDGEMENTS .................................................................................................... vi 1. Introduction .......................................................................................................................... 1 1.1. The cannabinoid system ...................................................................................................... 1 1.1.1. Cannabinoid receptors ...................................................................................................... 1 1.1.2. Lipid type endocannabinoids ........................................................................................... 2 1.1.3. Hemopressins (Pepcans), the putative peptide endocannabinoids ................................... 2 1.1.4. Phyto- and synthetic cannabinoids ................................................................................... 4 1.2. The opioid system ............................................................................................................... 5 1.2.1. Opioid receptors ............................................................................................................... 6 1.2.2. Endogenous opioids ......................................................................................................... 6 1.2.3. Phyto- and synthetic opioids ............................................................................................ 7 1.3. G-protein-coupled receptors and measurement assays ....................................................... 8 1.4. Synergistic interaction and multitargeting of the opioid and cannabinoid receptors .......... 9 2. Aims of the study ................................................................................................................ 11 3. Materials and Methods ...................................................................................................... 12 3.1. Chemicals .......................................................................................................................... 12 3.2. Analytical Methods ........................................................................................................... 12 3.3. Details of the preparation and analytical characterization of compounds 1-25 ................ 13 3.4. General procedure for the synthesis of the peptidic compounds in solution .................... 13 3.5. Preparation of hemopressins on solid support ................................................................... 13 3.6. Radiolabeling of JWH-018 ................................................................................................ 14 3.7. Radiolabeling of hemopressin(1–7) .................................................................................. 14 3.8. Preparation of brain membrane homogenates ................................................................... 15 3.9. Radioligand binding assays ............................................................................................... 15 3.10. Ligand stimulated [35S]GTPγS binding assay ................................................................. 16 3.11. Cell culture and permeability assay................................................................................. 17 3.12. Data analysis ................................................................................................................... 17 4. Results ................................................................................................................................. 19 4.1. Synthesis of monomeric and bivalent compounds ............................................................ 19 4.1.1. Oxycodone – JWH-018 bivalent compounds ................................................................. 19 4.1.2. Peptide– JWH-018 bivalent compounds ........................................................................ 21 4.2. Radiolabeling of JWH-018 ................................................................................................ 22 4.3. Characterization of the novel CB receptor radioligand [3H]JWH-018 ............................. 23 4.4. Radioligand binding studies .............................................................................................. 26 4.5. [35S]GTPγS functional binding assays .............................................................................. 30 4.6. Permeability of compounds 11 and 19 through the brain endothelium ............................ 38 4.7. Preparation and receptor binding properties of [3H]hemopressin(1-7) ............................. 39 4.8. Ligand stimulated [35S]GTPγS binding studies of hemopressins ..................................... 43 5. Discussion ............................................................................................................................ 46 6. Summary ............................................................................................................................. 49 7. References ........................................................................................................................... 51 Appendix ................................................................................................................................. 63 i LIST OF PUBLICATIONS List of thesis related publications: I. Dvorácskó, Sz., Keresztes, A., Mollica, A., Stefanucci, A., Macedonio, G., Pieretti, S., Zádor, F., Walter, F., Deli, M., Kékesi, G., Bánki, L., Tuboly, G., Horváth, Gy., Tömböly, Cs. Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors Eur. J. Med. Chem. in press (2019). IF: 4,816 II. Dvorácskó, Sz., Tömböly, Cs., Berkecz, R., Keresztes, A. Investigation of the receptor binding and functional characteristics of hemopressin(1-7). Neuropeptides 58, 15-22 (2016). IF: 2,915 III. Dvorácskó, Sz., Stefanucci, A., Novellino, E., Mollica, A. Design of multi target ligands for chronic and neuropathic pain. Future Med. Chem. 7, 2469-83 (2015). IF: 3,969 Other publications: 1. Mollica, A., Mirzaie, S., Costante, R., Carradori, S., Macedonio, G., Stefanucci, A., Dvorácskó, Sz., Novellino, E. Exploring the biological consequences of conformational changes in aspartame models containing constrained analogues of phenylalanine. J. Enzyme Inhib. Med. Chem. 31, 953-63 (2016). IF: 3,638 2. Monti, L., Stefanucci, A., Pieretti, S., Marzoli, F., Fidanza, L., Mollica, A., Mirzaie, S., Carradori, S., De Petrocellis, L., Schiano, M. A., Benyhe, S., Zádor, F., Szűcs, E., Ötvös, F., Erdei, A., Samavati, R., Dvorácskó, Sz., Tömböly, Cs., Novellino, E. Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates. J. Enzyme Inhib. Med. Chem. 31, 1638-47 (2016). IF: 3,638 3. Stefanucci, A., Costante, R., Macedonio, G., Dvorácskó, Sz., Mollica, A. Cysteine-, methionine- and seleno-cysteine-proline chimeras: Synthesis and their use in peptidomimetics design. Curr. Bioact. Comp. 12, 200-206 (2016). IF: 0 ii 4. Szűcs, E., Dvorácskó, Sz., Tömböly, Cs., Büki, A., Kékesi, G., Horváth, Gy., Benyhe, S. Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia. Neurosci. Lett. 633, 87-93 (2016). IF: 2,159 5. Mollica, A., Pelliccia, S., Famiglini, V., Stefanucci, A., Macedonio, G., Chiavaroli, A., Orlando, G., Brunetti, L., Ferrante, C., Pieretti, S., Novellino, E., Benyhe, S., Zádor, F., Erdei, A., Szűcs, E., Samavati, R., Dvorácskó, Sz., Tömböly, Cs., Ragno, R., Patsilinakos, A., Silvestri, R. Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors. J. Enzyme Inhib. Med. Chem. 32, 444–451 (2017). IF: 3,638 6. Nagy-Grócz, G., Zádor, F., Dvorácskó, Sz., Bohár, Zs., Benyhe, S., Tömböly, Cs., Párdutz, Á., Vécsei, L. Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine. Int. J. Mol. Sci. 18, e1617 (2017). IF: 3,687 7. Adamska-Bartłomiejczyk, A., Borics, A., Tömböly, Cs., Dvorácskó, Sz., Lisowski, M., Kluczyk, A., Wołczański, G., Piekielna-Ciesielska, J., Janecka, A. Synthesis, receptor binding studies, optical spectroscopic and in silico structural characterization of morphiceptin analogs with cis-4-amino-L-proline residues. J. Pept. Sci. 23, 864-870 (2017). IF: 1,969 8. Leone, S., Recinella, L., Chiavaroli, A., Martinotti, S., Ferrante, C., Mollica, A., Macedonio, G., Stefanucci, A., Dvorácskó, Sz., Tömböly, Cs., De Petrocellis, L., Vacca, M., Brunetti, L., Orlando, G. Emotional disorders induced by Hemopressin and RVD- hemopressin(α) administration in rats. Pharmacol. Rep. 69, 1247-1253 (2017). IF: 2,787 9. Ferrante, C., Recinella, L., Leone, S., Chiavaroli, A., Di Nisio, C., Martinotti, S., Mollica, A., Macedonio, G., Stefanucci, A., Dvorácskó, Sz., Tömböly, Cs., De Petrocellis, L., Vacca, M., Brunetti, L., Orlando, G. Anorexigenic effects induced by RVD-hemopressin(α)
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